PRODUCT INFORMATION ZYRTEC LEVOCABASTINE Eye Drops and Nasal Spray NAME OF MEDICINE Levocabastine hydrochloride DESCRIPTION Levocabastine, (-)-[3S-[1(cis), 3 alpha, 4 beta]]-1-[4-cyano-4-(4-fluorophenyl) cyclohexyl]-3- methyl-4-phenyl-4-piperidine-carboxylic acid monohydrochloride is a highly selective histamine H 1-antagonist for topical use. Levocabastine hydrochloride is a white powder, insoluble in water except at higher ph and only fairly soluble in other solvents such as acetone. CAS-79547-78-7 C 26H 29FN 2O 2.HCl MW: 456.99 ZYRTEC Levocabastine eye drops contain levocabastine hydrochloride equivalent to levocabastine 0.5 mg/ml as active ingredient, benzalkonium chloride and disodium edetate (both 0.15 mg/ml) as preservatives, and propylene glycol, polysorbate 80, sodium phosphate dibasic, sodium phosphate monobasic, hypromellose and water as inactive excipients in a sterile ophthalmic microsuspension (ph 6-8). ZYRTEC Levocabastine nasal spray contains levocabastine hydrochloride equivalent to levocabastine 0.5 mg/ml as active ingredient, benzalkonium chloride and disodium edetate (both 0.15 mg/ml) as preservatives and propylene glycol, polysorbate 80, sodium phosphate dibasic, sodium phosphate monobasic, hypromellose and water as inactive excipients. ZYRTEC Levocabastine nasal spray is available as a microsuspension (ph 6-8). PHARMACOLOGY Pharmacodynamics ZYRTEC Levocabastine eye drops contain levocabastine, a potent, fast-acting and highly selective histamine H 1-antagonist with a sustained duration of action. After topical application to the eyes, it almost immediately and for several hours relieves the typical symptoms of allergic conjunctivitis (itching, redness, chemosis, eyelid swelling, tearing). ZYRTEC Levocabastine nasal spray contains levocabastine, a potent, fast-acting and highly selective histamine H 1-antagonist with a sustained duration of action. After topical application to the nose, it almost immediately and for several hours relieves the typical symptoms of allergic rhinitis (sneezing, itchy nose, rhinorrhoea). Page 1 of 7 February 2017
Pharmacokinetics After intranasal and ocular application, the absorption of levocabastine is incomplete with a systemic bioavailability ranging from 60 to 80 for the nasal spray and from 30 to 60 for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are very low. Steady-state concentrations of levocabastine are attained within 7 to 10 days following multiple dosage and are predictable from single-dose pharmacokinetics. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. 70 of the parent drug is recovered unchanged in the urine, and 10 of the dose is excreted in the urine as the acylglucuronide of levocabastine. The remaining 20 is excreted unchanged in the faeces. After single intravenous dosing, levocabastine is rapidly distributed over the tissues, and the terminal half-life is 33 h. The total steady-state volume of distribution is 82 L (1.14 L/kg) with a total plasma clearance of 30 ml/min. Given the extremely low plasma concentrations after ocular application, a dose adjustment is unlikely to be required in patients with renal impairment receiving levocabastine eye drops. However, dose reduction should be considered in patients with renal disease during prolonged treatment with levocabastine nasal spray. As hepatic metabolism of levocabastine is negligible, dose adjustments in patients with impaired hepatic function should not be necessary. The plasma protein binding of levocabastine is 55 with albumin being the main binding protein. Special populations (1, 2) Elderly In the elderly, after multiple nasal administrations of 0.4mg levocabastine for 14 days, the terminal half-life of levocabastine was increased by 15 and the peak plasma level was increased by 26. Renal impairment After a single oral dose of 0.5mg levocabastine in solution, the terminal half-life of levocabastine in moderate to severe renal impairment (Creatinine Clearance 10 50mL/min) increased from 36 hours to 95 hours. Overall exposure to levobabastine based on AUC was increased by 56. INDICATIONS Eye Drops: Symptomatic treatment of seasonal allergic conjunctivitis. Nasal Spray: Symptomatic treatment of seasonal or perennial allergic rhinitis. Clinical Studies Clinical studies have shown that ZYRTEC Levocabastine eye drops and nasal spray are effective for the indications listed above. The duration of treatment with the eye drops alone was generally 2-4 weeks but lasted up to 3 months in two studies and 4 months in one study. Duration of treatment with the nasal spray alone was also generally 2-4 weeks, but lasted up to 10 weeks in some instances. The duration of treatment in studies using a combination of the eye drops and nasal spray was 8 weeks. CONTRAINDICATIONS Hypersensitivity to any of the ingredients. Page 2 of 7 February 2017
PRECAUTIONS Use with caution in the following circumstances Eye Drops: As with all ophthalmic preparations containing benzalkonium chloride, patients are advised not to wear soft (hydrophilic) contact lenses while under treatment with ZYRTEC Levocabastine eye drops. Use in patients with renal impairment Nasal Spray: Limited data are availale on the use of oral levocabastine. Caution should be exercised when administering ZYRTEC Levocabastine nasal spray to patients with renal impairment (refer to pharmacokinetics renal impairement). Paediatric use No data on use in children less than six years of age are available. Carcinogenicity/mutagenicity In female mice, dietary administration of levocabastine for 20 months stimulated the development of pituitary adenomas and mammary adenocarcinomas. The no-effect dose level for the pituitary tumours was 3 mg/kg/day, but a no-effect dose level has not been established for the mammary tumours. In female rats, there was an equivocal increase in the incidence of mammary tumours at the highest dose level of 34 mg/kg/day administered in the diet for 24 months. There was no evidence of carcinogenic activity in male rats or mice. The mechanism of the carcinogenic effects of levocabastine in female mice (and possibly rats) may involve antagonism of dopamine D 2-receptors in the pituitary gland and subsequent elevation of serum prolactin levels. Use in pregnancy Pregnancy Category B3. In pregnant rats, levocabastine readily crossed the placental barrier and was distributed extensively in foetal tissues. Reproductive studies in mice and rats showed that levocabastine was embryolethal at oral doses greater than 40 mg/kg/day in both species, and teratogenic at oral doses greater than 40 mg/kg/day in mice and 20 mg/kg/day in rats. The main foetal malformations observed were open eyes in mice, and polydactyly, hydrocephalus, anophthalmia/microphthalmia, hydronephrosis and arthrogryposis in rats. There are limited postmarketing data on the use of ZYRTEC Levocabastine eye drops or nasal spray in pregnant women. The risk for humans is unknown. Therefore, ZYRTEC Levocabastine eye drops and nasal spray should not be used during pregnancy. Use in lactation Based on determinations of levocabastine concentrations in saliva and breast milk in a nursing woman, who received a single oral dose of 0.5mg levocabastine, it is expected that approximately 0.6 of the total intranasally and approximately 0.3 of the total ophthalmically administered dose of levocabastine may be transferred to a nursing infant. However, due to the limited nature of the clinical and experimental data, it is recommended that ZYRTEC Levocabastine nasal spray or eye drops be avoided in breast-feeding mothers. Interactions with other drugs No interactions have been seen with ZYRTEC Levocabastine eye drops. With ZYRTEC Levocabastine nasal spray there were no reports of interaction with alcohol in clinical trials. In psychomotor performance studies there was no significant potentiation of the effects of alcohol on performance and subjective test measures with ZYRTEC Levocabastine nasal spray used at normal doses. Pharmacokinetic interactions The decongestant oxymetazoline may transiently reduce the absorption of nasal levocabastine. Page 3 of 7 February 2017
Co-administration of the CYP3A4 inhibitors ketoconazole (200mg) and erythromycin (333mg) as a single dose had no impact on the pharmacokinetics of intranasal levocabastine. Intranasal levocabastine did not change the pharmacokinetics of loratadine. Instructions to the patient Activities requiring alertness: In clinical trials there was no significant difference in the incidence of slowed patient reactions with ZYRTEC Levocabastine compared to placebo and active comparator drugs. ZYRTEC Levocabastine, therefore, would not be expected to interfere with the ability to drive a motor vehicle or operate machinery. Should drowsiness occur, caution is advised. ADVERSE EFFECTS Clinical Trial Data Eye Drops: The safety of ZYRTEC Levocabastine eye drops was evaluated in 508 subjects who participated in 4, placebo-controlled clinical trials and one open-label clinical trial. All adverse drug reactions (ADRs) reported by subjects in ZYRTEC Levocabastine eye drops clinical trials are presented in Table 1. Table 1: Adverse Drug Reactions Reported by ZYRTEC Levocabastine Eye Drops Treated Subjects in 5 Clinical Trials MedDRA System Organ Class MedDRA PT ZYRTEC Levocabastine (n=508) Placebo (n=178) Eye Disorders Eye Irritation 11.6 4.5 Nasal Spray: The safety of ZYRTEC Levocabastine nasal spray was evaluated in 2328 subjects who participated in 12 double-blind, placebo-controlled clinical trials. Adverse drug reactions (ADRs) reported in 1 of subjects in these trials are presented in Table 2. Table 2: Adverse Drug Reactions Reported by 1 ZYRTEC Levocabastine Nasal Spray Treated Subjects in 12 Double-Blind, Placebo-Controlled Clinical Trials MedDRA System Organ Class MedDRA PT ZYRTEC Levocabastine (n=2328) Placebo (n=1537) Gastrointestinal Disorders Nausea 1.3 1.2 General Disorders and Administrative Site Conditions Fatigue Pain 2.1 1.2 0.9 0.9 Infections and Infestations Sinusitis 1.8 0.9 Page 4 of 7 February 2017
Nervous System Disorders Headache Somnolence Dizziness Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal pain Epistaxis Cough 10.1 2.1 1.3 2.9 1.6 1.7 11.9 0.8 0.9 2.3 1.0 1.3 Additional ADRs reported for <1 of ZYRTEC Levocabastine Nasal Spray treated subjects in the 12 clinical trials are presented in Table 2. Table 2: Adverse Drug Reactions Reported by <1 ZYRTEC Levocabastine Nasal Spray Treated Subjects in 12 Double-Blind, Placebo-Controlled Clinical Trials MedDRA System Organ Class MedDRA PT General Disorders and Administrative Site Conditions Application site irritation Application site pain Application site dryness Application site burn Application site discomfort Respiratory, Thoracic, and Mediastinal Disorders Nasal discomfort Nasal congestion Postmarketing Data Additional adverse drug reactions first identified during postmarketing experience with ZYRTEC Levocabastine eye drops and nasal spray are included in Table 3 (nasal spray) and Table 4 (eye drops). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Therefore, the frequencies are provided according to the following convention (3,4): Very Common: 1/10 Common: 1/100 and < 1/10 Uncommon: 1/1000 and < 1/100 Rare: 1/10000 and < 1/1000 Very rare: 1/10000, including isolated reports In the tables below ADR s are presented by frequency category based on incidence in clinical trials or epidemiology studies when known. Page 5 of 7 February 2017
Table 3: Adverse Drug Reactions Identified During Postmarketing Experience with ZYRTEC Levocabastine Eye Drops by Frequency Category Estimated from Spontaneous Reporting Rates Cardiac Disorders Palpitations Eye Disorders Eye pain, Conjunctivitism Eyelid oedema, Eye swelling, Blepharitis, Ocular hyperaemia, Vision blurred General Disorders and Administrative Site Conditions Application site reaction including eye burning sensation, eye redness, eye pain, eye swelling, eye itching, watery eyes and vision blurred. Immune System Disorders Anaphylaxis, Angioneurotic oedema, Hypersensitivity Skin and Subcutaneous Tissue Disorders Contact dermatitis, Urticaria Nervous System Disorders Headache Table 4: Adverse Drug Reactions Identified During Postmarketing Experience with ZYRTEC Levocabastine Nasal Spray by Frequency Category Estimated from Spontaneous Reporting Rates Cardiac Disorders Eye Disorders General Disorders and Administrative Site Conditions Immune System Disorders Palpitations, Tachycardia Eyelid Oedema Malaise Anaphylaxis, Hypersensitivity Page 6 of 7 February 2017
Respiratory, Thoracic, and Mediastinal Disorders DOSAGE AND ADMINISTRATION Bronchospasm, Dyspnoea, Nasal oedema As ZYRTEC Levocabastine eye drops and nasal spray are available as a microsuspension, the bottle should be shaken before each application. Eye Drops: Adults and children 6 years of age and over: the usual dose is one drop of ZYRTEC Levocabastine eye drops per eye, twice daily. If necessary, the dose may be increased to one drop 3 to 4 times daily. The bottle should be well shaken before use. The duration of treatment should be limited to 8 weeks. Systemic absorption of levocabastine is very low. However, the systemic absorption of drugs from ophthalmic solutions can be minimised by pressure on the tear duct immediately after application. ZYRTEC Levocabastine eye drops should be used within one month of first opening of the bottle. Patients should be instructed to take appropriate measures to avoid contamination of the container. Nasal Spray: Adults and children 6 years of age and over: the usual dose is two sprays of ZYRTEC Levocabastine nasal spray per nostril, twice daily. If necessary, the dose may be increased to two sprays 3 to 4 times daily. The duration of treatment should be limited to 8 weeks. Patients should be instructed to clear the nasal passages prior to administering the spray and to inhale through the nose during spraying. Before using the pump delivery system for the first time, the pump reservoir should be filled by priming until a fine spray is delivered. OVERDOSE There has been no experience with overdose of ZYRTEC Levocabastine eye drops or nasal spray to date. After accidental intake of the contents of the bottle, sedation may occur. In case of overdose, the patient should be advised to drink plenty of water in order to accelerate the renal elimination of levocabastine. PRESENTATION ZYRTEC Levocabastine eye drops: 4 ml in 5 ml bottle. ZYRTEC Levocabastine nasal spray: 10 ml in 15 ml bottle. Storage ZYRTEC Levocabastine eye drops and nasal spray should be stored below 25 o C. SPONSOR Johnson & Johnson Pacific 45 Jones Street, Ultimo NSW 2007 Australia Date of initial TGA approval: 27 August 2014 Page 7 of 7 February 2017